Transcript Thyroid Hormones

Introduction to the Endocrine Module
October 20, 2015
Neil Gesundheit, M.D., M.P.H.
[email protected]
724-5454
Conflicts of Interest
I am a consultant to or have been a consultant to:
Pfizer, Inc., on the topic of smoking cessation
Vivus, Inc., on the topics of weight management and sexual dysfunction (I
am also a shareholder)
HealthEquityLabs.com on the topic of mobile health and disease prevention
HIPAA:
Patient photos shown in this presentation are either from the public domain
or are being used with patient permission
Module Logistics
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Endocrine physiology (60%), histology/pathology (25%), pharmacology (15%)
One endocrine tutorial: Tuesday, November 3 (Bone Physiology and Disorders) –
10:30-12:00pm tutorial; 12:00-12:30pm Q&A and “Meet the Professor” session
◦ Attendance is highly encouraged
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One required integrated pathology/physiology lab on Thursday, November 5,
10:30am-12:30pm
“Endocrine riddles” review sessions – NEW and fun – Fridays, October 23 and 30,
5:15-6:15 pm in LKSC 308
Two PBL case studies in POM
Module exam (Thursday, November 6)
Book resources: for endocrine physiology from lectures, syllabus, and Molina, Costanzo, or
Greenspan; for pathology, from lectures, syllabus, and Robbins; for pharmacology, from lectures,
syllabus, and Katzung
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Faculty/TAs (Katie Ransohoff for physiology: [email protected])
Syllabus
Katie, your TA
[email protected]
Specific Objectives of the Module
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Master the vocabulary of endocrinology
◦ the names of the hormones, where hormones are made, what organ or tissues they affect
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Learn the principles of endocrinology
◦ sensing mechanisms, feedback loops, regulation
◦ molecular and whole organ mechanisms of action
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Learn to identify endocrine structures microscopically and how tissues change in
endocrine disease states
Learn the pharmacology of drugs used to treat endocrine conditions
Learn “endocrine think” – how to analyze and solve problems based on logical
pathophysiological thinking
Objectives of this Lecture
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To discuss the functional organization of hormones
◦ their molecular structure and families
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To provide an introduction to the properties of hormones
◦ how hormones act; hormones as endogenous drugs
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Appreciate that endocrine disorders are visible to a discerning clinical eye:
case examples
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To appreciate the potential of endocrine therapeutics
◦ let’s cure Robert Wadlow, using a group-participatory format
What Are Hormones?
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The word “hormone” is derived from the Greek word meaning “arouse
the activity”
Endocrine hormones are endogenous chemical mediators that are
made at one site, enter the bloodstream, and affect the function of
distant organ or of an entire organism
◦ the “wi-fi internet of the human body”
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Paracrine hormones may act on nearby cells
Autocrine hormones act on the cells where they are made
Hormones at the Extremes:
GH Deficiency and Excess
Mr. and Mrs. Tom Thumb,
(Charles and Lavinia Stratton)
circa 1863
Hormones at the Extremes:
GH Deficiency and Excess
Mr. and Mrs. Tom Thumb,
(Charles and Lavinia Stratton)
circa 1863
The Alton Giant (Robert Wadlow),
circa 1936
What Functions Do Hormones Regulate?
GH, IGF-I, T/DHT/E2, insulin, cortisol,
T3/T4
Insulin, glucagon, leptin, cortisol,
T3/T4, Ghrelin, GLP-1
Insulin, cortisol, T3/T4, catecholamines
T/DHT, E2, progesterone, cortisol,
T3/T4
Vitamin D, PTH
Aldosterone, ADH, catecholamines,
cortisol, T3/T4
T3/T4, cortisol
Growth and development
Appetite and nutrition; lipids; overall
well-being
Regulation of intermediary metabolism
Libido, reproduction, lactation, gender
identity
[Ca++], integrity of bone
Blood pressure, volume regulation,
electrolyte balance
CNS development, mood
Org Chart for the Hormones
Steroid Hormones
Peptides
Glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
Estrogens (estradiol)
Progestins (progesterone)
Androgens (dihydrotestosterone)
Vitamin D [1,25(OH)2D3]
Insulin, IGF-I
Growth Hormone (GH)
Prolactin (PRL)
Hypothalamic Releasing Hormones
Somatostatin
Adrenocorticotropic Hormone (ACTH)
Thyroid-stimulating Hormone (TSH)
Thyrotropin-releasing Hormone (TRH)
Luteinizing Hormone (LH)
Follicle-stimulating Hormone (FSH)
Human Chorionic Gonadotropin (HCG)
Glucagon
Parathyroid Hormone
Others
Thyroid Hormones
T3 and T4
Amines
Epinephrine
Norepinephrine
Dopamine
Five Motifs for Receptor-Ligand Signal Transduction
(modified from Katzung 2004, Fig. 2-5)
Outside
Inside
Type
Intranuclear
Tyrosine
Kinase
Cytokine
Ion channel
Example(s)
Thyroid
Hormone
Insulin
Growth
Hormone
Acetylcholine
(at nicotinic R)
G-protein coupled
TSH/TRH
Five Motifs for Receptor-Ligand Signal Transduction
(modified from Katzung 2004, Fig. 2-5)
Outside
Inside
Type
Intranuclear
Tyrosine
Kinase
Cytokine
Ion channel
G-coupled
Example(s)
Thyroid
Hormone
Insulin
Growth
Hormone
Acetylcholine
(at nicotinic R)
TSH/TRH
Tyrosine Kinase Receptor-Ligand Signal Transduction
(modified from Katzung 2004, Fig. 2-7)
Insulin
+Insulin
-Insulin
Substrate
Substrate-P
Hypoglycemia After IV Insulin Infusion
Insulin 0.15 u/kg
Five Motifs for Receptor-Ligand Signal Transduction
(modified from Katzung 2004, Fig. 2-5)
Outside
Inside
Type
Intranuclear
Example(s) Thyroid
Hormone
Tyrosine
Kinase
Cytokine
Ion channel
G-coupled
Insulin
Growth
Hormone
Acetylcholine
(at nicotinic R)
TSH/TRH
Cytokine Receptor-Ligand Signal Transduction
(modified from Katzung 2004, Fig. 2-8)
GH molecule dimerizes receptor
Growth Hormone
JAK = Janus kinase (tyrosine kinase)
STAT = Signal transducers and activators of transcription
Five Motifs for Receptor-Ligand Signal Transduction
(modified from Katzung 2004, Fig. 2-5)
Outside
Inside
Type
Intranuclear
Example(s) Thyroid
Hormone
Tyrosine
Kinase
Cytokine
Ion channel
Insulin
Growth
Hormone
Acetylcholine
(at nicotinic R)
G-protein coupled
TSH/TRH
Signal Transduction in Receptors Coupled to G Proteins
(modified from Katzung 2004, Fig. 2-11)
Activates: adenylyl
cyclase
(cAMP)
PK-A or phospholipase
C
(DAG)
PK-C and
(IP3)
GTP
free Ca++
Crystal structure of the beta(2)
adrenergic receptor–Gs protein complex
Rasmussen, S.G., Devree, B.T., Zou, Y., Kruse, A.C., Chung, K.Y.,
Kobilka, T.S., Thian, F.S., Chae, P.S., Pardon, E., Calinski, D.,
Mathiesen, J.M., Shah, S.T., Lyons, J.A., Caffrey, M., Gellman, S.H.,
Steyaert, J., Skiniotis, G., Weis, W.I., Sunahara, R.K., and Kobilka,
B.K., Crystal structure of the beta(2) adrenergic receptor-Gs protein
complex. Nature 477, 549-555 (2011)
Org Chart for the Hormones
Steroid Hormones
Peptides
Glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
Estrogens (estradiol)
Progestins (progesterone)
Androgens (dihydrotestosterone)
Vitamin D [1,25(OH)2D3]
Insulin, IGF-I
Growth Hormone (GH)
Prolactin (PRL)
Erythropoietin (EPO)
Hypothalamic Releasing Hormones
Somatostatin
Adrenocorticotropic Hormone (ACTH)
Thyroid-stimulating Hormone (TSH)
Thyrotropin-releasing Hormone (TRH)
Luteinizing Hormone (LH)
Follicle-stimulating Hormone (FSH)
Human Chorionic Gonadotropin (HCG)
Glucagon
Parathyroid Hormone
Others
Thyroid Hormones
T3 and T4
Amines
Epinephrine
Norepinephrine
Dopamine
Summary: Hormones and Their Actions
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Hormones are named after activities they
subserve
Hormones bind to receptors and mediate
actions much in the way as drugs do with
their receptors
◦ One step, two step, three step
Hormones are Powerful Amplifiers
Hormone Production is Regulated
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The hypothalamus synthesizes several thousand
molecules of corticotropin-releasing hormone (CRH)
each day
The pituitary synthesizes several million molecules of
adrenocortico-trophic hormone (ACTH) each day
The adrenal glands make 4 mmoles (1017 molecules) of
cortisol each day
Cortisol is important to maintaining blood pressure,
blood glucose, appetite, growth
◦ its absence can be fatal
The Hypothalamic-PituitaryAdrenal (HPA) Axis in
Cushing’s Disease
Profile view of
a patient with
Cushing’s syndrome
Endocrine Diseases Present a Good Test of
Your Visual Recognition Skills
What is the finding?
What is the finding?
What is the finding?
What is the finding?
What is the finding?
What is the finding?
What is the finding?
Properties of Hormones
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Potent intercellular communicators
◦ Transmit signals at cell surface (amines, peptides, proteins) through protein
phosphorylation(s) or activation of second messengers; or in the nucleus
(steroids, T3) by binding to intracellular receptors and regulating transcription
◦ Hormone deficiency and excess can be devastating
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Amplifiers
Regulate and are regulated
Let’s Cure Robert Wadlow
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The facts
◦ Born 1918, Alton, IL: wt 8.7 lbs
◦ 1923 (age 5): 5’6” tall
◦ 1928 (age 10): 6’5” tall
◦ 1931 (age 13): 7’4” tall
◦ 1936 (h.s. graduation): >8’ tall
Robert Wadlow, The Alton Giant
Robert Wadlow at Summer Camp 1931 (age 13)
Robert Wadlow’s H.S. Graduation Photo (age 18)
Wilt Chamberlain in 4th Grade
Robert Wadlow Standing Next to his Brother, circa 1936
Let’s Cure Robert Wadlow
The Growth Axis
Hypothalamus
Somatostatin
GHRH
hypothalamus
(-)
hypothalamus
GH
Pituitar
y
pituitary
Liver
IGF-I
(+)
Group 2
Group 3
liver
T3/T4
cortisol
Growth Plate
Bone
Group 4
bone
E2/T
Group 1
nutrition